Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic ?-cell destruction due to the generation of reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules. Recent evidence has shown that ?-cell dysfunction is also an activate participant in T1D pathogenesis. We will compare pancreatic ?-cell functional identity changes that occur with T1D-prone Non-obese Diabetic (NOD) mice with T1D-resistant NOD.Ncf1m1J mice unable to generate NADPH oxidase (NOX)-derived superoxide. We will examine how the absence of ROS in NOD.Ncf1m1J mice can regulate ?-cell functional identity, interactions with immune cells, and delay in T1D. To corroborate our genetic mouse models, we will examine pancreatic b-cell responses following treatment with a pharmacological manganese metalloporphyrin antioxidant with human islets. Our overarching hypothesis is that reduction of ROS will preserve or enhance ?-cell functional identity, as defined by transcriptional signatures and insulin secretion in T1D-prone NOD mice and human islets. To address this hypothesis, the following independent and interrelated aims will be defined: (1) Define how genetic ablation of ROS preserves ?-cell functional identity. (2) Determine whether the absence of ROS can decrease pancreatic ?-cell-mediated inflammatory responses. (3) Determine whether antioxidant treatment preserves the function of mouse and human ?-cells. The insights gained from our studies will increase our understanding of diabetes etiology and may also point to future strategies employing antioxidant compounds to preserve and/or replace the function of pancreatic ?-cells.